The overall aim of this proposal is to answer two related questions about marrow stromal cells (MSCs): (1) do MSCs normally serve as a continuing source of precursor cells for renewal of many of the mesenchymal tissues of the body?; and (2) will further experiments in transgenic mice support preliminary observations, suggesting that systemic administration of MSCs can be used for cell replacement therapy and ex vivo gene therapy of osteogenesis imperfecta, and perhaps several other genetic diseases? The experimental protocols used to attempt to answer these two questions will be designed so that, if they produce positive results in transgenic mice, they can be subsequently used to design protocols for testing similar therapies, first in larger animals, and then in patients with osteogenesis imperfecta (OI) and related genetic diseases. The Specific Aims are: (1) to further define the tissue fate of MSCs that are infused systemically into mice, by preparing MSCs expressing marker genes driven by tissue-specific promoters, and infusing these cells into irradiated and non-irradiated mice; and (2) to determine the degree to which the OI phenotype can be rescued in transgenic mice expressing a mutated COL1A1 gene, by administration of MSCs from normal mice, and MSCs over-expressing a normal COL1A1 allele.